Dosage Regimen for the Treatment of Multiple Sclerosis with a S1P Receptor Modulator

ABSTRACT

The present application relates to a dosage regimen of an S1P receptor modulator or agonist in the course of the treatment of patients suffering from an inflammatory or autoimmune disease or disorder, for example multiple sclerosis (MS).

FIELD OF THE PRESENT APPLICATION

The present application relates to a dosage regimen of an S1P receptormodulator or agonist in the course of the treatment of patientssuffering from an inflammatory or autoimmune disease or disorder, forexample multiple sclerosis (MS).

Multiple sclerosis is the chief cause of neurological disability inyoung adults and the most common demyelinating disorder of the centralnervous system. Available therapies such as interferon-ß and glatirameracetate have modest efficacy and marginal effects on the progression ofdisability. These biological agents are administered parenterally andare associated, e.g., with injection site reactions and pyreticsymptoms, such as flu-like symptoms. Therefore, there is a strongmedical need for a safe and effective oral treatment of multiplesclerosis.

Of those people with multiple sclerosis who receive treatment, asignificant number continue to experience disease activity clinically orexperience side effects that include flu-like symptoms. Immediatepost-injection reactions and injection site reactions. As a result, asubstantial population of patients are untreated. Including many withactive disease. These MS patients have either tried an existing therapybut discontinued due to intolerance, adverse effects, or perceived lackof efficacy or have not started any therapy because of their concernwith adverse effects, fear of self-injection, fear of needles, or beliefthat currently available options are not effective enough to warranttrial. Thus, there is a significant unmet need for effective newtherapies in MS, which limit or reduce the possible adverse events orside effects.

S1P receptor modulators are compounds which signal as agonists at one ormore sphingosine1-phosphate receptors, e.g. S1P1 to S1P5. Agonistbinding to a S1P receptor may e.g. result in dissociation ofintracellular heterotrimeric G-proteins into Gα-GTP and Gßγ-GTP, and/orincreased phosphorylation of the agonist-occupied receptor andactivation of downstream signaling pathway kinases.

S1P receptor modulators are valuable compounds for the manufacture ofmedication for the treatment of various conditions in mammals,especially in human beings. For example, efficacy in transplantation hasbeen demonstrated in rats (skin, heart, liver, small bowel), dogs(kidney), and monkeys (kidney) models. Due to their immune-modulatingpotency, S1P receptor modulators are also useful for the treatment ofinflammatory and autoimmune diseases. Treating such diseases usuallyrequires prolonged taking of medication, and maintaining the adequatedrug regimen overtime.

Oral Fingolimod is the first compound in the new class of therapeuticscalled sphingosine 1-phosphate receptor modulators. Fingolimod isbelieved to reduce the number of lymphocytes circulating in the bloodstream by reversibly trapping a proportion of them in the lymph nodes.Consequently, the number of activated lymphocytes reaching the brain isdecreased, resulting in reduced inflammatory destruction. This is a newmechanism of action for MS.

Oral Siponimod is another compound in the new class of therapeuticscalled sphingosine 1-phosphate receptor modulators. Siponimod isbelieved to reduce the number of lymphocytes circulating in the bloodstream by reversibly trapping a proportion of them in the lymph nodes.Consequently, the number of activated lymphocytes reaching the brain isdecreased, resulting in reduced inflammatory destruction.

FTY720 efficacy in the treatment of multiple sclerosis has been shown inhumans (e.g. as described in “FTY720 therapy exerts differential effectson T call subsets in multiple sclerosis”. Mehling M, et al., Neurology.2008 Oct. 14; 71(16):1281-7; and “Oral Fingolimod (FTY720) for relapsingmultiple sclerosis”. Kappos L, Antel J, Comi G, Montalban X, O'Connor P,Polman C H, Haas T, Kom A A, Karisson G, Radue E W; FTY720 D2201 StudyGroup. N Engl J Med. 2006 Sep. 14; 355(11):1124-40.).

Administration of a S1P receptor modulator, such as Fingolimod orSiponimod, may induce adverse events, such as a transient reduction ofthe heart rate and cardiac conduction at treatment initiation. Inparticular it has been described that administration of 1.25 mg ofBAF-312 may induce a decrease in heart rate of approximately 8 beets/min(“FTY720: Placebo-Controlled Study of the Effect on Cardiac Rate andRhythm in Healthy Patients”, Robert Schmouder, Denise Serra, Yibin Wang,John M. Kovarik, John DiMarco, Thomas L. Hunt and Marie-Claude Bastien.J. Clin. Pharmacol. 2006; 46; 895.).

Because of such a possible adverse event, administration of the compoundto the patients may have to be made under full and constant medicalcontrol, in order to check that the cardiac rhythm is maintained at anacceptable level and no high degree atrioventricular block occurs.Patients may have to stay in hospitals which complicate the treatmentand increase the costs of treatment occurrence of adverse events duringa drug treatment may induce patient hospitalization or prolongation ofexisting hospitalization.

Such possible events may also cause the patients to interrupt theirtreatment, change the recommended dosing regimen on their own or takethe medication on an irregular basis, without any medical support orrecommendation for doing that. While it is paramount for treatinginflammatory or autoimmune diseases, such as for example multiplesclerosis, that the adequate medication is taken over a long period oftime, sometimes during the whole life of the patient, and the adequatedrug regimen is kept over such a long period of time.

Therefore, there is a need to reduce or manage the possible adverseevents which may be generated by administration of such a S1P receptormodulator, while administering a dosage which is adequate to treat orprevent the disease for which the compound is administered during therequired period of treatment.

More specifically, there is a need to provide an efficient treatment fortreating an inflammatory or autoimmune disease or disorder, such asmultiple sclerosis, for a large population of multiple sclerosispatients, including patients who could be more exposed or more sensitiveto said possible adverse events, patients who were never treated ordiagnosed for an inflammatory or autoimmune disease or disorder

There is furthermore a need to ameliorate patient compliance.

BRIEF DISCLOSURE

Surprisingly it has been found that by administering a S1P receptormodulator or agonist, such as Siponimod, according to the specificdosage regimen or method of treatment of the present application, it ispossible to treat the patient efficiently while controlling, reducing orabolishing the possible adverse events, e.g. side effects, which may beassociated with administration of such a compound.

A further benefit is that the dosing regimen and methods of treatment ofthe present application permit to administer a S1P receptor modulator oragonist, such as Siponimod, to patients who otherwise may have beenreluctant or not could not have been instructed to take that medication.In particular they permit to treat patients suffering from aninflammatory or autoimmune disease or disorder, such as multiplesclerosis, for which the ratio risk/benefit may otherwise be lessfavorable. Such patients are for example patients susceptible to orsuffering from one or more disease or disorders affecting the heart orheart rhythm, respiratory functions, eyes, hepatic functions. This alsoconcerns patients that have undergone an interruption or treatmentholiday in the maintenance dosage regime e.g. a holiday of greater than10 days.

Furthermore the dosing regimen and methods of treatment of the presentapplication is applicable for patients who were already under treatmentfor an inflammatory or autoimmune or disease, for example undertreatment for multiple sclerosis, as well as patients who were nevertreated or were not diagnosed for an inflammatory or autoimmune ordisease before taking a S1P receptor modulator or agonist.

The dosage regimen of the present application is a regimen for a S1Preceptor modulator or agonist therapy, which enables administration of atherapeutic dosage range of the S1P receptor to be achieved withcontrolled or minimal side effects, which could otherwise have beenpossibly associated with S1P receptor modulator therapy.

Another benefit of the present application is to provide an therapeuticregimen for an inflammatory or autoimmune or disease, such as multiplesclerosis, which can be personalized, e.g. adapted to the specificprofile of the patient to be treated and/or to the state of the diseasein this patient, in such a way that that the disease is treated (or thedisease severity is reduced), while the adverse events which couldotherwise have been associated with administering said S1P receptormodulator or agonist are controlled, reduced, or abolished. For example,therapeutic regimen of the present application may be personalized inview of the other diseases or disorders the patient could be affectedwith, the other medication he could be taken, e.g. depending on whetherhe is suffering from a heart disease or disorder.

In one embodiment, a method is provided for treating relapsing remittingmultiple sclerosis in a patient in need thereof, the method comprising:

(a) identifying a patient suffering from relapsing remitting multiplesclerosis at risk of contracting infection caused by varicella zostervirus by testing said patient for a history of infection caused byvaricella zoster virus,

(b) vaccinating the patient at risk of contracting infection caused byvaricella zoster virus, and

(c) administering orally Siponimod or a pharmaceutically acceptable saltthereof to said patient at a daily dosage of 2 mg, thereby limiting therisk of infection caused by varicella zoster virus, wherein therelapsing remitting multiple sclerosis is treated by the administrationof Siponimod. Treating may reduce the frequency of clinicalexacerbations. The Siponimod may be administered as a hydrochloridesalt. The infection may be chickenpox.

In another embodiment, a method is provided for treating multiplesclerosis in a patient in need thereof, the method comprising:

(a) identifying a patient suffering from multiple sclerosis at risk ofcontracting infection caused by varicella zoster virus by testing saidpatient for a history of infection caused by varicella zoster virus,

(b) vaccinating the patient at risk of contracting infection caused byvaricella zoster virus, and

(c) administering orally a therapeutically effective amount of Siponimodor a pharmaceutically acceptable salt thereof to said patient,

thereby limiting the risk of infection caused by varicella zoster virus,

wherein the multiple sclerosis is treated by the administration ofSiponimod. The multiple sclerosis may be primary progressive multiplesclerosis. The Siponimod may be administered in a dosage of 0.25 mgtwice per day or a dosage of 2 mg per day.

DETAILED DISCLOSURE S1P Receptor Modulators or Agonists

The present application encompasses S1P receptor modulators, agonists,and antagonists. In some embodiments, the S1P receptor modulators,agonists, and antagonists are compounds as described in U.S. Pat. Nos.7,939,519 and 8,492,441.

In a preferred embodiment of the present application, the S1P receptormodulator is Siponimod. In the present application, Siponimod may bereferred to as by its IUPAC name, which is:

1-({4-[(1E)-1-({[4-Cyclohexyl-3(trifluoromethyl)phenyl]methoxy}imino)ethyl]-2-ethylphenyl}methyl)azetidine-3-carboxylicacid.

In the present application, Siponimod may also be referred to by itstrade name, MAYZENT. In the present application, Siponimod may also bereferred to by the designation BAF-312.

In the present application, Siponimod may also be referred to bychemical structure, shown below:

It will be understood by a person of ordinary skill in the art that suchdesignations of Siponimod are interchangeable, and each designationrefers to the same compound.

Other preferred embodiments of the present application includepharmaceutically acceptable salts, prodrugs, or stereoisomers ofSiponimod.

Another specific S1P receptor modulator of the present application isthe phosphorylated derivative of Siponimod, also referred to asSiponimod-phosphate.

Preferably, the S1P receptor modulator or agonist of the presentapplication, e.g. Siponimod in free form, in a pharmaceuticallyacceptable salt form or Siponimod-phosphate, is administered orally.

Dosage Regimen

As previously stated, the present application provides a new dosageregimen and method for treating an inflammatory or autoimmune disease ordisorder in a patient in need thereof, comprising administering to saidpatient a S1P receptor modulator or agonist, such as Siponimod(BAF-312), a phosphate derivative thereof or a pharmaceuticallyacceptable salt thereof, in such a way that the disease is treated orthe disease severity is reduced, while the adverse events possiblyassociated with administration of said S1P receptor modulator or agonistare controlled, limited, reduced or abolished. For example there isprovided a method for treating an inflammatory or autoimmune disease ordisorder in a patient in need thereof, comprising administering to saidpatient a S1P receptor modulator or agonist, such Siponimod (BAF-312), aphosphate derivative thereof or a pharmaceutically acceptable saltthereof, in such a way that the symptoms of the disease are reduced orabolished while the adverse events possibly associated withadministration of said S1P receptor modulator or agonist are controlled,limited, reduced or abolished.

According to the present application there is provided a method foradministering BAF-312, a phosphate derivative thereof or apharmaceutically acceptable salt thereof, to a patient in need thereofpreferably refers to a method for treating an inflammatory or autoimmunedisease or disorder, limiting the symptoms associated thereof or theprogression thereof, e.g. multiple sclerosis, in a patient in needthereof. In particular it refers to a method for treating RRMS, limitingthe symptoms associated thereof or the progression thereof in a patientin need thereof.

According to the present application the terms “treatment” or “treat”refer to both prophylactic or preventive treatment as well as curativeor disease-modifying treatment, including treatment of patients at riskof contracting the disease or disorder, or suspected to have contractedthe disease or disorder, as well as patients who are ill or have beendiagnosed as suffering from the disease or disorder.

Autoimmune diseases or disorders according to the present applicationare preferably chronic long-term diseases, e.g. multiple sclerosis (MS),for example relapsing remitting multiple sclerosis (RRMS) or primaryprogressive multiple sclerosis (PPMS), e.g. RRMS. MS takes severalforms, with new symptoms occurring either in discrete attacks (relapsingforms) or slowly accumulating over time (progressive forms).

The dosing regimens and methods of treatment according to the presentapplication are particularly adapted for multiple sclerosis, e.g. RRMS.

As herein defined, treating multiple sclerosis refers to, but is notlimited to, reducing the frequency of clinical exacerbations or delayingthe accumulation of physical disability induced by multiple sclerosis.It may also refer to limiting the symptoms of the disease.

As herein defined, symptoms or disorders associated with multiplesclerosis encompass neurological symptoms, physical and cognitivedisability and neuropsychiatric disorders.

As herein defined, adverse event refers to any adverse change in healththat occurs to a patient receiving a treatment or within a specifiedperiod of time after the treatment has been completed. Controlling theadverse events refers to limiting the extension, outcome, consequencesor impact of such events in such a way that the patient's health is nota risk, or the treatment can be continued without worsening the overallhealth of the patient. The adverse events are not necessarily related tothe medication itself; they may also be related to the inflammatory orautoimmune disease or disorder for which the patient is treated oranother disease or disorder that the patient is further affected with.

According to the present application, reduction of the adverse eventsrefers to the reduction of the events, e.g. of side-effects, to a levelthat is acceptable to the patient safety, e.g. which does not requirespecific treatment and/or specific medical care, hospitalization ormedical monitoring. For example, reduction of the adverse events refersto the reduction of the events to a level that is acceptable for thepatient compliance.

According to the present application, limitation of the adverse eventsrefers to limitation of the number or occurrence of adverse events, e.g.of side-effects, in a patient, to a number or occurrence which isacceptable to the patient, e.g. which does not require specifictreatment and/or specific medical care, hospitalization or medicalmonitoring. For example, limitation of the adverse events refers tolimitation of the number or occurrence of adverse events to a number oroccurrence that is acceptable for the patient safety end/or compliance.

The monitoring of possible adverse events may be done as describedherein above. For example, it may be done by ophthalmic examination,dermatologic examination, pulmonary function tests, chest X-ray and/orCT, Holter monitoring, and/or echocardiography. In a specific embodimentof the present application, the monitoring and reporting of adverseevents comprises the monitoring and reporting of bradycardia, syncope orpre-syncope, serious infectious, liver toxicity, and macular edema.

As herein defined, a patient treated with Siponimod (BAF-312) refers toa patient receiving Siponimod (BAF-312), a phosphate derivative thereof(i.e. Siponimod-phosphate) or a pharmaceutically acceptable saltthereof, for treating an inflammatory or autoimmune disease or disorderaccording to the present application, e.g. MS, e.g. RRMS.

As herein defined, a patient in need of prescribing Siponimod refers toa patient suffering from an inflammatory or autoimmune disease ordisorder according to the present application, e.g. a MS patient.

Patients treated with Siponimod (BAF-312) and the patients in need ofprescribing Siponimod may be patients who have never received treatmentfor an inflammatory or autoimmune disease or disorder, such as patientswho have never received a treatment for treating or preventing MS, aswell as patients who previously received one or more treatment for aninflammatory or autoimmune disease or disorder, for example whopreviously received one or more treatment for MS.

The effectiveness of the S1P modulator of the present application intreating multiple sclerosis may be evaluated by medical standards andcriteria known to the skilled person. For example, it can be evaluatedthrough annual relapse rate of multiple sclerosis.

For example, the dosage of the S1P receptor modulator or agonist of thepresent application can be considered as efficient for treating thedisease or reducing the symptoms associated thereof, e.g. for treatingmultiple sclerosis, when the relapse rate is decreased by more than 45%,e.g. more than 50%, e.g. more than 80%.

In another embodiment effectiveness of the S1P receptor modulator oragonist of the present application in treating multiple sclerosis isevaluated through the disability progression, e.g. according to theKurtzke Expanded Disability Status Scale (EDSS). The Kurtzke ExpandedDisability Status Scale (EDSS) is a method of quantifying disability inmultiple sclerosis. The EDSS quantifies disability in eight FunctionalSystems (FS) and allows neurologists to assign a Functional System Score(FSS) in each of these. For example, the dosage of the S1P receptormodulator or agonist of the present application can be considered asefficient for treating the disease or reducing the symptoms associatedthereof, e.g. for treating multiple sclerosis, when progression of thepatient disability is delayed by at least 25%, e.g. by at least 30%,e.g. by at least 32%.

The effectiveness of the dosing regimen of the present application mayalso be evaluated by measuring brain lesions. e.g. by Magnetic ResonanceImaging (RMI) scans.

Monitoring

The present application provides a dosing regimen and a method fortreating an inflammatory or autoimmune disease or disorder in a patientin need thereof, comprising administering to said patient atherapeutically effective amount of a S1P receptor modulator or agonist,wherein said method comprises the steps of

-   -   i) monitoring the patient during a specific period of time after        the first administration of said S1P receptor modulator or        agonist, and    -   ii) optionally interrupting the administration of said S1P        receptor modulator or agonist and/or modifying the treatment        regimen thereof and/or administering a second drug which        mitigates said possible adverse events.

Such a dosing regimen is particularly adapted for administeringSiponimod, e.g. in a patient suffering from multiple sclerosis.

Furthermore, there is provided a S1P receptor modulator or agonist, e.g.BAF-312, a phosphate derivative thereof or a pharmaceutically acceptablesalt thereof, for use in the treatment of an inflammatory or anautoimmune disease or disorder, e.g. multiple sclerosis, wherein saidtreatment comprises the steps of

-   -   i) monitoring the patient during a specific period of time after        the first administration of said S1P receptor modulator or        agonist, and    -   ii) optionally interrupting the administration of said S1P        receptor modulator or agonist and/or modifying the treatment        regimen thereof and/or administering a second drug which        mitigates said possible adverse events.

In a specific embodiment, the present application provides BAF-312, aphosphate derivative thereof or a pharmaceutically acceptable saltthereof, e.g. the hydrochloride salt of BAF-312, for use in thetreatment of multiple sclerosis, wherein said treatment comprises thesteps of

-   -   i) monitoring the patient during a specific period of time after        the first administration of BAF-312, a phosphate derivative        thereof or a pharmaceutically acceptable salt thereof, and    -   ii) optionally interrupting the administration of BAF-312, a        phosphate derivative thereof or a pharmaceutically acceptable        salt thereof, and/or modifying the treatment regimen thereof,        and/or administering a second drug which mitigates said possible        adverse events.

The present application further pertains to a S1P receptor modulator oragonist, e.g. BAF-312, a phosphate derivative thereof or apharmaceutically acceptable salt thereof, for use in a method fortreating an inflammatory or an autoimmune disease or disorder, e.g.multiple sclerosis, wherein said method comprises the steps of

-   -   i) monitoring the patient during a specific period of time after        the first administration of said S1P receptor modulator or        agonist, and    -   N) optionally interrupting the administration of said S1P        receptor modulator or agonist and/or modifying the treatment        regimen thereof and/or administering a second drug which        mitigates said possible adverse events.

In a specific embodiment, the present application pertains to BAF-312, aphosphate derivative thereof or a pharmaceutically acceptable saltthereof for use in a method for the treatment of multiple sclerosis,wherein said treatment comprises the steps of

-   -   i) monitoring the patient during a specific period of time after        the first administration of said S1P receptor modulator or        agonist, and    -   ii) optionally interrupting the administration of said S1P        receptor modulator or agonist and/or modifying the treatment        regimen thereof and/or administering a second drug which        mitigates said possible adverse events.

According to the present application, the action taken on step ii)depends on the results obtained under step i).

When the S1P receptor modulator or agonist is selected from Siponimod(BAF-312), a phosphate derivative thereof or a pharmaceuticallyacceptable salt thereof, the step of modifying the treatment regimen mayconsist of administering a daily dosage of the drug that is lower thanabout 2 mg and then increasing the dosage up to a daily dosage of about2 mg. The daily dosage of the drug may then be increased stepwise, e.g.by titration. It may also consist of administering a daily dosage of thedrug higher than 2 mg, e.g. a daily dosage of about 3 mg or about 4 mgor about 5 mg or about 6 mg.

In a specific embodiment of the present application, e.g. when the S1Preceptor modulator or agonist is selected from Siponimod (BAF-312), aphosphate derivative thereof or a pharmaceutically acceptable saltthereof, the step of modifying the treatment regimen may consist ofincreasing the period of time between two consecutive administrations ofthe medication.

According to the present application, there is provided a patientmonitoring, i.e. a specific monitoring of patients treated with a S1Preceptor modulator or agonist, such as Siponimod (BAF-312), a phosphatederivative thereof or a pharmaceutically acceptable salt thereof, inorder to control, limit or abolish the possible adverse events, whereinsaid monitoring is performed before and/or during administration of themedication.

The patient monitoring of the present application comprises

-   -   a) monitoring infections or infestations, e.g. viral infections,        throughout administering said S1P receptor modulator or agonist,        and/or    -   b) performing an ophthalmologic examination.

The patient monitoring may further comprise one or more steps of

-   -   c) monitoring the heart rate of the patient at least during the        first hours after the first administration of said S1P receptor        modulator or agonist,    -   d) observing the patient during the first hours after the first        administration of said S1P receptor modulator or agonist, to        monitor the heart rate of the patient,    -   e) performing liver function tests,    -   f) performing dermatological examinations,    -   g) performing pulmonary functions tests.

The patient monitoring may further comprise one or more steps of

-   -   h) determining complete blood counting (CBC),    -   i) lymphocytes counting and/or recording of blood key        parameters,    -   j) monitoring and/or recording of vital signs, e.g. heart rate,        blood pressure, e.g. arterial blood pressure.    -   k) monitoring and/or recording of cardiac disorders,    -   l) monitoring and/or recording of other adverse events or        side-effects.

The present application also provides a dosing regimen and a method ofcontrolling, reducing, or abolishing the possible adverse eventsassociated with treating a patient suffering from an inflammatory orautoimmune disease or disorder with a S1P receptor modulator or agonist,comprising administering to said patient a therapeutically effectiveamount of said S1P receptor modulator or agonist, wherein said methodcomprises i) a patient monitoring as defined herein above, and

-   -   ii) optionally interrupting the administration of said S1P        receptor modulator or agonist and/or modifying the treatment        regimen thereof.

In one embodiment of the present application, the patient monitoring ofthe present application may comprise one or more of the following steps,optionally all the steps of,

-   -   complete blood counting (CBC),    -   lymphocytes counting,    -   analysis of liver enzymes,    -   monitoring and/or recording of vital signs, e.g. heart rate,        blood pressure, e.g. arterial blood pressure,    -   testing history of viral infection or viral serology, e.g.        regarding chickenpox.    -   monitoring and/or recording of infections or infestations, e.g.        viral infections,    -   dermatological examinations,    -   ophthalmologic examinations,    -   examinations of pulmonary function,    -   monitoring and/or recording of cardiac disorders,    -   monitoring and/or recording of blood key parameters,    -   monitoring and/or recording of liver function tests,    -   monitoring and/or recording of other adverse events or        side-effects.

Preferably, the patient monitoring of the present application comprisesone or more of the following steps, optionally all the steps of:

-   -   complete blood counting (CBC),    -   analysis of liver enzymes,    -   ophthalmologic examinations, and    -   testing history of viral infection or viral serology, e.g.        regarding chickenpox,    -   monitoring and/or recording of infections or infestations, e.g.        viral infection.

The patient monitoring of the present application may further comprise

-   -   establishing an electrocardiogram (ECG), e.g. at starting        administration with the medication, and/or    -   vaccinate the patient before starting administration, e.g.        against varicella zoster virus (VZV).

As herein defined, the patient monitoring of the present application maycomprise or more of the above described monitoring steps.

In one embodiment of the present application, the patient monitoringcomprises the steps of

-   -   monitoring and/or recording of infections or infestations, e.g.        viral infections,    -   performing ophthalmologic examinations, and optionally further        comprises the steps of    -   monitoring and/or recording of cardiac disorders for specific        category of patients, and/or    -   performing dermatological examinations.

In another embodiment of the present application, the patient monitoringcomprises the steps of

-   -   monitoring end/or recording of infections or infestations, e.g.        viral infections,    -   ophthalmologic examinations.    -   monitoring and/or recording of cardiac disorders. e.g. for        specific category of patients,    -   liver function tests;    -   and optionally further comprises the steps of    -   dermatological examinations.

In yet a further embodiment of the present application, the patientmonitoring comprises the steps of

-   -   monitoring the heart rate of the patient,    -   monitoring and/or recording of infections or infestations, e.g.        viral infections,    -   performing ophthalmologic examinations,    -   and optionally further comprises the steps of    -   performing dermatological examinations.

In yet another embodiment of the present application, the patientmonitoring comprises the steps of

-   -   monitoring and/or recording of infections or infestations, e.g.        viral infections,    -   performing an ophthalmologic examination within the first 1 to        10 after starting administration,    -   observing patients for at least 6 hours after the first dose        administration, and optionally further comprises the steps of    -   dermatological examinations.

The patient monitoring may further comprise a step of monitoring and/orrecording of liver function tests in case patients develop symptomssuggestive of hepatic dysfunction.

In a preferred embodiment of the present application, there is provideda method of prescribing Siponimod (BAF-312), a phosphate derivativethereof or a pharmaceutically acceptable salt thereof, to a patient inneed thereof, in such a way as to limit the possible adverse eventsbefore or during administration of Siponimod, wherein said methodcomprises the patient monitoring as herein above described.

For example, the method of prescribing Siponimod may comprise one ormore of the following steps:

-   -   performing lymphocyte counting,    -   monitoring and/or recording of vital signs, e.g. blood pressure,        e.g. arterial blood pressure,    -   monitoring and/or recording of infections or infestations, e.g.        viral infections,    -   performing dermatological examinations,    -   performing ophthalmologic examinations,    -   performing examinations of pulmonary function,    -   monitoring and/or recording of cardiac disorders,    -   monitoring and/or recording of blood key parameters, e.g. level        of serum ALT,    -   performing liver function tests,    -   monitoring and/or recording of other adverse events or        side-effects, and    -   wherein each of said steps is performed for a specific period of        time before and/or during the period of administering the drug.

The specific and regular monitoring of the treated patients may consistof one or more of the following steps

-   -   performing lymphocyte counting,    -   monitoring and/or recording of vital signs, e.g. blood pressure,        e.g. arterial blood pressure,    -   monitoring and/or recording of infections or infestations, e.g.        viral infections,    -   performing dermatological examinations,    -   performing ophthalmologic examinations,    -   performing examinations of pulmonary function,    -   monitoring and/or recording of cardiac disorders,    -   monitoring and/or recording of blood key parameters, e.g. level        of serum ALT,    -   performing liver function tests,    -   monitoring and/or recording of other adverse events or        side-effects, and    -   wherein said steps are performed for a specific period of time        before and/or during the period of administering the drug.

Each step may be performed as further explained below.

Preferably, the patient monitoring may consist of one or more of thefollowing steps:

-   -   monitoring and/or recording of infections or infestations, e.g.        viral infections, during FTY720 therapy,    -   ophthalmologic examinations as herein defined,    -   monitoring and/or recording of cardiac disorders for specific        category of patients,    -   liver function tests in case patients develop symptoms        suggestive of hepatic dysfunction,    -   and optionally further comprises the steps of    -   dermatological examinations.

The different steps the patient monitoring of the present applicationare performed at a specific period of time after administration of thefirst dose.

These steps can be performed as described herein.

In a specific embodiment of the present application, the treatedpatients are monitored under supervision of medical doctors for aspecific period of time after the first dose administration, for thefirst 1 to 10 hours after the first administration of the S1P receptormodulator or agonist, e.g. Siponimod, a phosphate derivative thereof ora pharmaceutically acceptable salt thereof, for at least 6 hours afterthe first dose administration.

According to the present application, one or more of these steps, e.g.monitoring and/or recording of cardiac disorders, are performed at least4 hours after the first dose administration, e.g. at least for 6 hoursafter the first dose administration, or at least 8 hours alter the firstdose administration, e.g. 3 to 8 hours after the first doseadministration, e.g. 4 to 6 hours after the first dose administration,e.g. 4 to 6 hours after the first dose administration. Preferablymonitoring and/or recording of cardiac disorders are performed about 6hours after the first dose administration The step of monitoring and/orrecording of cardiac disorders may consist of observing patients duringthat period of time after the first dose administration, e.g. during atleast 4 hours after the first dose administration, e.g. at least for 6hours after the first dose administration, or at least 8 hours after thefirst dose administration.

According to the present application, the cardiac disorders which aremonitored and/or recorded comprise but are not limited to bradycardiaand high-grade AV block.

According to the present application, the infections which are recordedor monitored are for example viral infections, e.g. varicella zostervirus (VZV), influenza viral infection, herpes viral infection, lowerrespiratory tract infection, e.g. bronchitis and pneumonia.

In an embodiment of the present application, the monitoring ofinfections or infestations is performed within the first three monthsafter the first dose administration, e.g. within the first two monthsafter the first dose administration. In another embodiment of thepresent application, the monitoring of infections or infestations isperformed throughout administration of the medication.

Prior to starting to administer the S1P receptor modulator or agonist,the patient may be tested for history of infections, e.g. viralinfection, in particular chickenpox. In case the searched serology isnegative, the patient may be vaccinated, e.g. against varicella zostervirus or influenza virus.

The monitoring or recording of infections or infestations, e.g. viralinfections, may be performed with medical techniques available, forexample through complete blood counting (CBC) and/or lymphocytescounting.

According to the present application, the ophthalmologic examinationpreferably comprises the checking and/or monitoring of disturbances invisual acuity, e.g. appearance of macular edema.

In a specific embodiment of the present application, eye examinationsinclude at least one of eye history, visual acuity, dilatedophthalmoscopy, Optical Coherence Tomography (OCT), evaluation of thefundus. Such examinations are preferably performed by anophthalmologist.

According to the present application, ophthalmologic examination may beperformed after initiating the administration with S1P receptormodulator or agonist, e.g. after commencing BAF-312 therapy, e.g. withinthe first 1 to 12 months, e.g. 2 to 10 months, e.g. 2 to 6 months, e.g.2 to 5 months, e.g. 3 to 4 months. Additional ophthalmologicexaminations may be performed as needed based on patient symptoms, e.g.at intervals determined by the ophthalmologist.

According to the present application, the ophthalmologic examination maycomprising the steps of

-   -   1) identifying the eye diseases history of the patient to be        treated before commencing the treatment with BAF-312,    -   2) having ophthalmologic examinations performed as herein above        mentioned, e.g. 3 to 4 months after commencing the treatment        with BAF-312, preferably by an ophthalmologist, and optionally    -   3) having additional ophthalmologic examinations performed based        on patient symptoms, e.g. at intervals determined by the        ophthalmologist.

Ophthalmologic examination may also be performed before starting theadministration with S1P receptor modulator or agonist, e.g. beforestarting BAF-312 therapy. This embodiment is particularly adapted forspecific patients' categories, for example in case of patients who havean eyes disease or disorder, and/or history of diabetes or uveitis.

According to the present application, the dermatological examination maycomprise the checking of appearance e.g. of neoplasms, skinmalignancies, melanoma, squamous cell carcinoma, basal cell carcinoma.Dermatological screening may be performed prior to, or shortly afterinitiation of therapy. In a specific embodiment of the presentapplication, dermatological screenings are performed annually in patientreceiving the S1P receptor modulator or agonist, e.g. BAF-312, aphosphate derivative thereof or a pharmaceutically acceptable saltthereof.

Dermatological screening may be performed by a physician, e.g. adermatologist. In another embodiments, such screening is performed morefrequently, e.g. by the patient himself.

According to the present application, the examinations of pulmonaryfunction may be performed by spirometry, pulmonary function tests, e.g.FEV1, FVC, FEF25-75%, DLCO, diffusion capacity for carbon monoxide, orchest high resolution computed tomography (HRCT).

In a specific embodiment of the present application the pulmonaryfunction test (PFT) is performed a few hours to a few days after thefirst administration, for example at the day of the firstadministration, for example from 2 to 12 hours after the first drugadministration, for example from 2 to 8 hours after the first drugadministration, for example from 2 to 6 hours after the firstadministration, for example at 6-hour after the first administration. Asecond PFT may be performed a few days after the first administration,for example from 2 to 10 days after the first drug administration, forexample from 3 to 8 days first drug administration, for example about aweek after the first drug administration.

In a specific embodiment of the present application the level of liverenzyme, e.g. serum ALT, is evaluated at initiation of therapy andoptionally periodically thereafter. Continuous evaluation isparticularly adapted in case of patients who develop symptoms suggestiveof hepatic dysfunction.

According to the present application, the liver function tests may beperformed for specific category of patients, e.g. patients who developsymptoms suggestive of hepatic dysfunction, e.g. nausea, vomiting,abdominal pain, anorexia, or jaundice.

According to the present application, monitoring and/or recording ofliver function tests may comprise any one of the steps of

-   -   1) identifying the level of liver enzyme, e.g. serum ALT, in the        patient to be treated before the first administration of the S1P        receptor modulator or agonist, e.g. BAF-312, a phosphate        derivative thereof or a pharmaceutically acceptable salt        thereof, and administering the first dose only if alanine        aminotransferase (ALT) level is not more than 2 times the upper        limit of the normal range (ULN),    -   2) identifying the level of liver enzyme, e.g. serum ALT, in the        patient under therapy, and discontinue the therapy in patients        experiencing jaundice or elevation of liver enzyme is more than        5 times the upper limit of the normal range (ULN).

The patient monitoring of the present application may comprise a step ofobserving the patient for the first 1 to 10 hours after the firstadministration of the S1P receptor modulator or agonist, e.g. Siponimod,a phosphate derivative thereof or a pharmaceutically acceptable saltthereof, e.g. the first 2 to 8 hours after the first administration,e.g. the first 3 to 9 hours after the first administration, e.g. thefirst 2 to 8 hours after the first administration, e.g. the first 4 to 7hours after the first administration, e.g. the first 6 hours, e.g. thefirst 5 hours, e.g. the first 4 hours after the first administration ofsaid S1P receptor modulator or agonist, e.g. Siponimod, a phosphatederivative thereof or a pharmaceutically acceptable salt thereof. Forexample, the patient monitoring of the present application may comprisea step of observing the patient at least 2 hours after the firstadministration of said S1P receptor modulator or agonist, e.g.Siponimod, a phosphate derivative thereof or a pharmaceuticallyacceptable salt thereof. e.g. at least 4 hours after the firstadministration, e.g. at least 6 hours after the first administration.

According to the present application, there is provided a method fortreating an inflammatory or autoimmune disease or disorder in a patientin need thereof, comprising administering to said patient atherapeutically effective amount of S1P receptor modulator or agonist,wherein specific parameters of the patient are checked before initiatingsaid treatment, and if necessary, the treatment regimen is adaptedand/or a second drug which mitigates the adverse events which couldpossibly occur.

The present application further pertains to a S1P receptor modulator oragonist, e.g. BAF-312, a phosphate derivative thereof or apharmaceutically acceptable salt thereof, for use in a method oftreating an inflammatory or an autoimmune disease or disorder, e.g.multiple sclerosis, wherein said method comprises the steps of checkingspecific parameters of the patient before initiating said treatment, andif necessary adapting the treatment regimen thereof and/or administeringa second drug which mitigates the adverse events which could possiblyoccur.

Said parameters are selected from signs of infections or infestations(e.g. viral infections), visual acuity, presence of eye disease, liverenzymes, blood pressure, blood analysis (e.g. complete blood count),electrocardiogram (ECG), pulmonary function, presence of skin disease ordisorder, and liver function.

In a specific embodiment, these parameters are selected from signs ofinfections or infestations (e.g. viral infections), visual acuity, liverenzymes and blood pressure, and optionally heart rate.

For example, an ECG is performed before initiating administration withsaid S1P receptor modulator or agonist.

These parameters may also be checked throughout the treatment with saidS1P receptor modulator or agonist.

In a specific embodiment of the present application there is provided

-   -   1-a method for administering a S1P receptor modulator or        agonist, e.g. Siponimod, a phosphate derivative thereof or a        pharmaceutically acceptable salt thereof, in a patient in need        thereof, comprising the steps of    -   a.) identifying the eye diseases history of the patient to be        treated before commencing the treatment with said S1P receptor        modulator or agonist,    -   b.) having ophthalmologic examinations performed as herein above        mentioned, e.g. 3 to 4 months after commencing the treatment        with said S1P receptor modulator or agonist, preferably by an        ophthalmologist, and optionally    -   c.) having additional ophthalmologic examinations performed        based on patient symptoms, e.g. at intervals determined by the        ophthalmologist.    -   2—A method for treating an inflammatory or autoimmune disease or        disorder (for example multiple sclerosis), and limiting the        symptoms associated thereof or reducing the severity of the        disease, in a patient in need thereof, comprising the steps a.),        b.) and c.) as defined above.    -   3—a S1P receptor modulator or agonist, e.g. BAF-312, a phosphate        derivative thereof or a pharmaceutically acceptable salt        thereof, for use in a method for treating an inflammatory or an        autoimmune disease or disorder, e.g. multiple sclerosis, wherein        said method comprises the steps a.), b.) and c.) as defined        above.    -   4—a S1P receptor modulator or agonist, e.g. BAF-312, a phosphate        derivative thereof or a pharmaceutically acceptable salt        thereof, for use in the treatment of an inflammatory or an        autoimmune disease or disorder, e.g. multiple sclerosis, wherein        said treatment comprises the steps a.), b.) and c.) as defined        above.    -   5—BAF-312, a phosphate derivative thereof or a pharmaceutically        acceptable salt thereof, e.g. the hydrochloride salt of BAF-312,        for use in a method for the treatment of multiple sclerosis,        wherein said treatment comprises the steps of    -   a′) identifying the eye diseases history of the patient to be        treated before commencing the treatment with BAF-312, phosphate        derivative or pharmaceutically acceptable salt thereof,    -   a.) having ophthalmologic examinations performed as herein above        mentioned, e.g. 3 to 4 months after commencing the treatment        with BAF-312, phosphate derivative or pharmaceutically        acceptable salt thereof, preferably by an ophthalmologist, and        optionally    -   b.) having additional ophthalmologic examinations performed        based on patient symptoms, e.g. at intervals determined by the        ophthalmologist.    -   6—BAF-312, a phosphate derivative thereof or a pharmaceutically        acceptable salt thereof, e.g. the hydrochloride salt of BAF-312,        for use in the treatment of multiple sclerosis, wherein said        treatment comprises the steps a′.), b′.) and c′.) as defined        above.

In a specific embodiment of the present application there is provided

-   -   7—A method for administering a S1P receptor modulator or        agonist, e.g. Siponimod, a phosphate derivative thereof or a        pharmaceutically acceptable salt thereof, in a patient in need        thereof, comprising the steps of    -   d) identifying the level of liver enzyme, e.g. serum ALT, in the        patient to be treated before the first administration of said        S1P receptor modulator or agonist, and administering the first        dose only if ALT level is not >2√óULN, and    -   e) identifying the level of liver enzyme, e.g. serum ALT, in the        patient under therapy, and discontinue the therapy in patients        experiencing jaundice or elevation of liver enzyme >5√óULN.    -   8—A method for treating an inflammatory or autoimmune disease or        disorder (for example multiple sclerosis), and limiting the        symptoms associated thereof or reducing the severity of the        disease, in a patient in need thereof, comprising the steps d.),        and e.) as defined above.    -   9—A S1P receptor modulator or agonist, e.g. BAF-312, a phosphate        derivative thereof or a pharmaceutically acceptable salt        thereof, for use in a method for treating an inflammatory or an        autoimmune disease or disorder, e.g. multiple sclerosis, wherein        said method comprises the steps d.), and e.) as defined above.    -   10—A S1P receptor modulator or agonist, e.g. BAF-312, a        phosphate derivative thereof or a pharmaceutically acceptable        salt thereof, for use in the treatment of an inflammatory or an        autoimmune disease or disorder, e.g. multiple sclerosis, wherein        said treatment comprises the steps d.), and e.) as defined        above.    -   11—BAF-312, a phosphate derivative thereof or a pharmaceutically        acceptable salt thereof, e.g. the hydrochloride salt of BAF-312,        for use in a method for the treatment of multiple sclerosis,        wherein said method comprises the steps of    -   d′) identifying the level of liver enzyme, e.g. serum ALT, in        the patient to be treated before the first administration of        BAF-312, a phosphate derivative thereof or a pharmaceutically        acceptable salt thereof, and administering the first dose only        if ALT level is not >2xULN, and    -   e′) identifying the level of liver enzyme, e.g. serum ALT, in        the patient under therapy, and discontinue the therapy in        patients experiencing jaundice or elevation of liver enzyme        >5xULN    -   12—BAF-312, a phosphate derivative thereof or a pharmaceutically        acceptable salt thereof, e.g. the hydrochloride salt of BAF-312,        for use in the treatment of multiple sclerosis, wherein said        treatment comprises the steps d′.), and e′.) as defined above.

In yet another embodiment of the present application there is provided

-   -   13—A method for administering a S1P receptor modulator or        agonist, e.g. BAF-312, a phosphate derivative thereof or a        pharmaceutically acceptable salt thereof, in a patient in need        thereof and receiving concomitant beta-blocker therapy,        comprising the steps of    -   f) measuring heart rate and/or blood pressure of the patient to        be treated before commencing the treatment with said S1P        receptor modulator or agonist,    -   g) either measuring heart rate every 3 to 5 hour, e.g. every        four hour, for at least 6-hour hereafter, and/or perform an ECG        3 to 6 hours, e.g. 4 to 6 hours, post-dose, and    -   h) administering an adequate treatment if        bradyarrhythmia-related symptom is seen under step g), e.g.        atropine or isoprenaline.

In one embodiment, that method refers to a method for administeringBAF-312, a phosphate derivative thereof or a pharmaceutically acceptablesalt thereof, e.g. the hydrochloride salt of BAF-312, in a patientaffected by multiple sclerosis.

-   -   14—A method for treating an inflammatory or autoimmune disease        or disorder (for example multiple sclerosis), and limiting the        symptoms associated thereof or reducing the severity of the        disease, in a patient in need thereof, comprising the steps f.),        g.) and h.) as defined above.    -   15—A S1P receptor modulator or agonist, e.g. BAF-312, a        phosphate derivative thereof or a pharmaceutically acceptable        salt thereof, for use in a method for treating an inflammatory        or an autoimmune disease or disorder, e.g. multiple sclerosis,        wherein said method comprises the steps f.), g.) and h.) as        defined above.    -   16—A S1P receptor modulator or agonist, e.g. BAF-312, a        phosphate derivative thereof or a pharmaceutically acceptable        salt thereof, for use in the treatment of an inflammatory or an        autoimmune disease or disorder, e.g. multiple sclerosis, wherein        said treatment comprises the steps f.), g.) and h.) as defined        above.    -   17—BAF-312, a phosphate derivative thereof or a pharmaceutically        acceptable salt thereof, e.g. the hydrochloride salt of BAF-312,        for use in a method for the treatment of multiple sclerosis,        wherein said method comprises the steps of    -   f′) measuring heart rate and/or blood pressure of the patient to        be treated before commencing the treatment with BAF-312, a        phosphate derivative thereof or a pharmaceutically acceptable        salt thereof,    -   g′) either measuring heart rate every 3 to 5 hour, e.g. every        four hour, for at least 6-hour hereafter, and/or perform an ECG        3 to 6 hours, e.g. 4 to 8 hours, post-dose, and    -   h′) administering an adequate treatment if        bradyarrhythmia-related symptom is seen under step g), e.g.        atropine or isoprenaline.    -   18—BAF-312, a phosphate derivative thereof or a pharmaceutically        acceptable salt thereof, e.g. the hydrochloride salt of BAF-312,        for use in the treatment of multiple sclerosis, wherein said        treatment comprises the steps of f.), g′.) and h′.) as defined        above.

In yet another embodiment of the present application there is provided

-   -   19—A method for administering a S1P receptor modulator or        agonist, e.g. BAF-312, a phosphate derivative thereof or a        pharmaceutically acceptable salt thereof, in a patient in need        thereof, comprising the steps of    -   i) observing the patient after the first dose administration for        an observing period as defined hereinabove, e.g. for at least 6        hours    -   j) measuring heart rate of the patient after this period,    -   k) either releasing the patient if the if the is >40 bpm, or of        40-60 bpm e.g. in case this value is not the lowest heart rate        measured during the 6-hour observation period; or maintaining        the patient in an appropriate setting.

Such a method is particularly adapted to patients with low resting heartrate (e.g. lower than 50) or those taking beta blockers, or having highgrade atrioventricular (AV) block or sick-sinus syndrome.

In a specific embodiment, that method refers to a method foradministering BAF-312, a phosphate derivative thereof or apharmaceutically acceptable salt thereof, e.g. the hydrochloride salt ofBAF-312, in a patient affected by multiple sclerosis.

The present application also provides

-   -   20—BAF-312, a phosphate derivative thereof or a pharmaceutically        acceptable salt thereof, e.g. the hydrochloride salt of BAF-312,        for use in the treatment of multiple sclerosis, wherein said        treatment comprises the steps i.), j.) and k.) as defined above.    -   21—BAF-312, a phosphate derivative thereof or a pharmaceutically        acceptable salt thereof, e.g. the hydrochloride salt of BAF-312,        for use in a method of treating multiple sclerosis, wherein said        method comprises the steps i.), j.) and k.) as defined above.

In specific cases, e.g. when patients experiencing symptomatic eventsassociated with bradyarrhythmia not resolved by the end of the 6-hourobservation, day 2 dose may also be performed with an observation periodlike the first administration, e.g. as described above.

An observation period as defined hereinabove, e.g. 6 hour observation,may also be performed in case of a patient restarting the S1P receptormodulator or agonist, e.g. BAF-312, a phosphate derivative thereof or apharmaceutically acceptable salt thereof, after a drug interruption ofmore than 4 days, e.g. more than 6 days, e.g. more than 8 days, e.g.more than 10 days, e.g. more than 12 days, e.g. more than 14 days, e.g.more than 18 days, e.g. more than 21 days.

In another embodiment of the present application, there is provided amethod for administering BAF-312, a phosphate derivative thereof or apharmaceutically acceptable salt thereof, to a patient in need thereofwhile controlling, limiting or abolishing the possible adverse eventsassociated or in relation to such an administering, wherein the patientsat possible risk of showing such events are identified beforeadministering the drug and specific and regular monitoring of thetreated patients is performed, e.g. by an adequate physician.

The patients at possibly increased risk may be patients selected frompatients who have eyes diseases or disorders; patients who show a highALT level, patients who have hepatic dysfunction, patients who havehypertension; and patients who have heart failure or arrythmias. It mayalso concern patient affected by asthma, for example moderate asthmaand/or diabetic patients.

In another embodiment, it can be pregnant women.

As herein defined, an eyes disease or disorder refers to a disease ordisorder impacting eyes, e.g. uveitis, diabetes.

Patients who show a high ALT level refers to patients who show an ALTlevel of, or superior to, 2 times than ULN, e.g. before initiatingBAF-312 treatment)

Patients who have heart disorders refers to one or more disordersselected from high-grade AV block, sick sinus syndrome, ischemic heartdisease, congestive heart failure, and arrhythmia. For example, thisconcerns patients suffering from or at risk of bradyarrhythmia, patientswith high grade atrioventricular blocks or sick sinus syndrome, patientswith a history of syncopal episodes, or patients under beta blockers oranti-arrhythmic treatment, such as patients under anti-arrhythmic drugs.

According to the present application, there is provided a specificmonitoring of patients treated with a S1P receptor modulator or agonist,e.g. BAF-312, a phosphate derivative thereof or a pharmaceuticallyacceptable salt thereof, wherein said patients are suffering from aninflammatory or an autoimmune disease or disorder. e.g. multiplesclerosis, comprising any ones of the following steps of:

-   -   i) observation period, e.g. at least 6 hour, e.g. 4 to 6 hours,        during which or at the end of which heart rate is checked, as        defined herein,    -   ii) annual skin examination after first dose administration, as        defined herein,    -   iii) regular review of liver enzyme, e.g. serum ALT, as defined        herein,    -   iv) ophthalmologic examinations 2 to 12 months, e.g. 3 to 4        months, after first dose administration, as defined herein,    -   v) regular checking of patient visual function, as defined        herein.

There is further provided method of administering a S1P receptormodulator or agonist, e.g. Siponimod in the form of BAF-312, a phosphatederivative thereof or a pharmaceutically acceptable salt thereof, topatients suffering from an inflammatory or an autoimmune disease ordisorder, e.g. multiple sclerosis, comprising

-   -   a) performing any ones of the following steps of:    -   i) observation period, e.g. at least 6 hour, e.g. 4 to 6 hours,        during which or at the end of which heart rate is checked, as        defined herein,    -   ii) annual skin examination after first dose administration, as        defined herein,    -   iii) regular review of liver enzyme, e.g. serum ALT, as defined        herein,    -   iv) ophthalmologic examinations 3 to 4 months after first dose        administration, as defined herein,    -   v) regular checking of patient visual function, as defined        herein;    -   and    -   b) if required, interrupting Siponimod administration based upon        the results of one of more of the above steps or changing the        treatment regimen and/or administering a second drug. Step b)        may correspond to appearance of adverse events. The second drug        may be a drug which mitigates said possible adverse events.

Interrupting Siponimod administration, changing the treatment regimenand/or administering a second drug, may occur in case of any of thefollowing conditions: bradycardia or atrioventricular conductionabnormalities, macular edema or other visual disturbance, skin cancer,altered liver functions or liver injury, infections or hypertension.Duration of the interruption is defined by the physician.

Interrupting Siponimod administration, changing the treatment regimenand/or administering a second drug, may also occur in case thelymphocyte count of the patient becomes abnormally low, or becomes lowerthan 2001 mL.

For example, step a) may comprise one or more steps of

-   -   i) monitoring the heart rate of the patient,    -   ii) monitoring infections or infestations, e.g. viral        infections, and    -   iii) performing ophthalmologic examination within the first 1 to        10 after starting administration.

Therapeutic Dosages

In a preferred embodiment of the present application the methods foradministering BAF-312, a phosphate derivative thereof or apharmaceutically acceptable salt thereof as defined herein above, inparticular the methods for treating an inflammatory or autoimmunedisease or disorder, limiting the symptoms associated thereof or theprogression thereof, e.g. multiple sclerosis, in a patient in needthereof comprise administering a daily dosage of BAF-312, a phosphatederivative thereof or a pharmaceutically acceptable salt thereof, e.g.BAF-312 hydrochloride, of not more than 2 mg, e.g. of about 2 mg.

According to the present application there is provided a compoundselected from Siponimod (BAF-312), a phosphate derivative thereof or apharmaceutically acceptable salt thereof, e.g. Siponimod hydrochloride,for use in treating or preventing an inflammatory or autoimmune disease,whereby said compound is administered in such a way to a patient thatthe adverse events possibly associated with administration of saidcompound are controlled, limited, reduced or abolished. For example, thedaily dosage of Siponimod (BAF-312), a phosphate derivative thereof or apharmaceutically acceptable salt thereof, e.g. Siponimod hydrochloride,does not exceed 2 mg, e.g. is of about 2 mg.

In a specific embodiment of the present application there is provided amethod for treating multiple sclerosis, controlling or limiting thesymptoms associated thereof or reducing the severity of said disease ina patient in need thereof, comprising administering a daily dosage ofSiponimod (BAF-312), a phosphate derivative thereof or apharmaceutically acceptable salt thereof, e.g. Siponimod hydrochloride,wherein said daily dosage does not exceed 2 mg, e.g. is of about 2 mg,and wherein the patient is further affected by asthma (for examplemoderate asthma), by a disease or disorder impacting eyes or has anhistory of eyes diseases or disorders (for example is affected byuveitis or diabetes), show high-grade AV block, sick sinus syndrome,hepatic dysfunction or hypertension.

In a further embodiment of the present application there is provided amethod for treating multiple sclerosis, controlling or limiting thesymptoms associated thereof or reducing the severity of said disease ina patient in need thereof, comprising administering a daily dosage ofSiponimod (BAF-312), a phosphate derivative thereof or apharmaceutically acceptable salt thereof, e.g. Siponimod hydrochloride,wherein said daily dosage does not exceed 2 mg, e.g. Is of about 2 mg,and wherein the patient is pregnant.

In yet a further embodiment of the present application there is provideda method for treating multiple sclerosis, limiting the symptomsassociated thereof or reducing the severity of said disease in a patientin need thereof, comprising administering a daily dosage of Siponimod(BAF-312), a phosphate derivative thereof or a pharmaceuticallyacceptable salt thereof, e.g. Siponimod hydrochloride, wherein saiddaily dosage does not exceed 2 mg, e.g. is of about 2 mg, and whereinthe patient is a MS patients who has never received treatment for MS,e.g. do novo patient.

According to the present application, adopting the treatment regimen mayconsist of decreasing the dosage, or increasing the time between twoconsecutive administrations of the S1P receptor modulator or agonist,e.g. Siponimod, a phosphate derivative thereof or a pharmaceuticallyacceptable salt thereof. For example, it may consist of administering0.25 mg of Siponimod, a phosphate derivative thereof or apharmaceutically acceptable salt thereof, two times a day. It may alsoconsist of increasing stepwise the dosage of the drug during the firstperiod of administration up to a daily dosage of 2 mg or 1 mg, e.g.adopting a stepwise administration, e.g. a titration.

The present application pertains to a method for treating multiplesclerosis comprising

-   -   (a) administering a varied dose of a drug selected from the        group consisting of Siponimod (BAF-312), a phosphate derivative        thereof or a pharmaceutically acceptable salt thereof in a        patient in need thereof,    -   (b) monitoring adverse events occurring in said patient,    -   (c) monitoring reduction or abolition of symptoms associated        with multiple sclerosis, and    -   (d) determining optimal dose for said patient

The daily dose of the drug may be not exceeding 2 mg.

In another embodiment, the daily dose of the drug is above 2 mg, e.g. isabout 3.00 mg, e.g. about 4.00 mg, e.g. about 5.00 mg.

There is also provided a S1P receptor modulator or agonist, e.g.BAF-312, a phosphate derivative thereof or a pharmaceutically acceptablesalt thereof, for use in a method for treating an inflammatory orautoimmune disease, e.g. multiple sclerosis, wherein said methodcomprises

-   -   (a) administering a varied dose of said S1P receptor modulator        or agonist in a patient in need thereof,    -   (b) monitoring adverse events occurring in said patient,    -   (c) monitoring reduction or abolition of symptoms associated        with said inflammatory or autoimmune disease, and    -   (d) determining optimal dose for said patient.

This method is particularly adapted for BAF-312, a phosphate derivativethereof or a pharmaceutically acceptable salt thereof, e.g. BAF-312hydrochloride, for treating multiple sclerosis.

When the S1P receptor modulator or agonist is selected from BAF-312, aphosphate derivative thereof or a pharmaceutically acceptable saltthereof, e.g. is BAF-312 hydrochloride, and the disease is multiplesclerosis, the daily dose of the drug may not be exceeding 2 mg.

In another embodiment, the S1P receptor modulator or agonist is selectedfrom BAF-312, a phosphate derivative thereof or a pharmaceuticallyacceptable salt thereof, e.g. BAF-312 hydrochloride, and the daily doseis exceeding 2 mg, e.g. is about 3 mg, e.g. about 4 mg, e.g. about 5 mg.

In yet a further embodiment of the present application, there isprovided a personalized method for treating an inflammatory orautoimmune disease or disorder, e.g. multiple sclerosis, in a patient inneed thereof comprising administering to said patient a therapeuticallyeffective amount of a S1P receptor modulator or agonist,

wherein said method comprises

-   -   (a) administering a varied dose of said drug to the patient,    -   (b) monitoring adverse events occurring in said patient,    -   (c) monitoring reduction or abolition of symptoms associated        with multiple sclerosis, and    -   (d) determining optimal dose for said patient,

wherein said regimen is adapted for treating said disease or disorderand controlling, reducing, or abolishing the possible adverse eventsassociated with administering said S1P receptor modulator or agonist.

The steps (a) to (d) above may also be used in a method for determininga personalized therapeutic treatment regimen of a drug selected from thegroup consisting of Siponimod (BAF-312), a phosphate derivative thereofor a pharmaceutically acceptable salt thereof, in a patient sufferingfrom an inflammatory or autoimmune disease, e.g. multiple sclerosis.

The present application also pertains a compound selected from BAF-312,a phosphate derivative thereof or a pharmaceutically acceptable saltthereof, e.g. BAF-312 hydrochloride, for use in a method for treating aninflammatory or autoimmune disease or disorder in a patient in needthereof, wherein said method is personalized, e.g. is adapted fortreating said disease or disorder to the specific profile of the patientin such a way that the adverse events associated with administering saidS1P receptor modulator or agonist are controlled, reduced, or abolished.In such a case, the patient to be treated may be selected from patientswho have never received treatment for that disease or disorder, patientssuffering or at risk of heart failure or arrythmias, patients affectedby asthma, patients who have eyes diseases or disorders, hepaticdysfunction or hypertension.

The present application provides for a compound selected from BAF-312, aphosphate derivative thereof or a pharmaceutically acceptable saltthereof, e.g. BAF-312 hydrochloride, for use in treating patientssuffering from an inflammatory or an autoimmune disease or disorder,e.g. multiple sclerosis, wherein the compound is administered throughthe administration pattern defined above.

The present application also provides for a compound selected fromBAF-312, a phosphate derivative thereof or a pharmaceutically acceptablesalt thereof, e.g. BAF-312 hydrochloride, for use in treating patientssuffering from an inflammatory or an or disorder disease, e.g. multiplesclerosis, wherein the compound is administered through the patientmonitoring defined above.

Combination

In another embodiment of the present application, the S1P receptormodulator, e.g. Siponimod (BAF-312), a phosphate derivative thereof or apharmaceutically acceptable salt thereof, e.g. Siponimod hydrochloride,is administered together with a second drug which mitigates the possibleadverse event associated with administration of Siponimod.

Such a second drug may be administered only in the event that an adverseevent, e.g. a side-effect, occurs or increases in intensity or frequencyto a level which is not acceptable anymore, e.g. as hereinabovedescribed.

The second drug may be selected from the group consisting of drugs whichtreat or prevent macular edema, anti-cancer agents (e.g.chemotherapeutic agents), anti-infection agents, anti-hypertensivedrugs, anti-bradychardia agents, and mixture thereof.

Examples of second drug include, but are not limited to, calcium channelblocker (e.g. diltiazem), atenolol, valsartan,

When the S1P receptor modulator or agonist of the present application,e.g. Siponimod (BAF-312), a phosphate derivative thereof or apharmaceutically acceptable salt thereof, e.g. Siponimod hydrochloride,is administered together with a second drug which mitigates the possibleadverse event associated with administration of Siponimod, the dailydosage of said S1P receptor modulator or agonist may be above 2 mg, e.g.may be about 3 mg, e.g. about 4 mg, e.g. about 5 mg.

For example there is provided a combination, e.g. a kit, containing aS1P receptor modulator or agonist of the present application, e.g.Siponimod (BAF-312), a phosphate derivative thereof or apharmaceutically acceptable salt thereof, e.g. Siponimod hydrochloride,and a second drug which is selected from the group consisting ofanti-cancer agents, anti-infection agents, anti-microbial agents,anti-viral therapy, and anti-hypertensive drugs, whereby the dosage ofsaid S1P receptor modulator or agonist is above 2 mg, e.g. is about 3 mgor about 4 mg or about 5 mg or about 6 mg.

The present application also provides a specific dosage regimen ofBAF-312 for treating an inflammatory or autoimmune disease or disorder,limiting the symptoms associated thereof or the progression thereof,e.g. multiple sclerosis, in a patient in need thereof, comprisingadministering to said patient a daily dosage of Siponimod (BAF-312), aphosphate derivative thereof or a pharmaceutically acceptable saltthereof, which leads to a reduction of peripheral lymphocyte count ofabout 70 to 75%, e.g. of about 73%, 75% or 76%.

In another embodiment the present application provides a specific dosageregimen of BAF-312 for treating an inflammatory or autoimmune disease ordisorder, limiting the symptoms associated thereof or the progressionthereof, e.g. multiple sclerosis, in a patient in need thereof,comprising administering to said patient a daily dosage of Siponimod(BAF-312), a phosphate derivative thereof or a pharmaceuticallyacceptable salt thereof, which leads to a reduction of peripherallymphocyte count to a level low enough to obtain the therapeutic effecton the disease while controlling, limiting or abolishing the incidenceof infections. Preferably this daily dosage is not more than 2 mg ofSiponimod (BAF-312), a phosphate derivative thereof or apharmaceutically acceptable salt thereof, e.g. of the hydrochloride saltthereof

Utility of the dosage regimen of the present application in treatingdiseases and conditions as hereinabove specified may be demonstrated instandard animal or clinical tests, e.g. in accordance with the methodsdescribed hereinafter.

1. A method for treating relapsing remitting multiple sclerosis in apatient in need thereof, the method comprising: (a) identifying apatient suffering from relapsing remitting multiple sclerosis at risk ofcontracting infection caused by varicella zoster virus by testing saidpatient for a history of infection caused by varicella zoster virus, (b)vaccinating the patient at risk of contracting infection caused byvaricella zoster virus, and (c) administering orally Siponimod or apharmaceutically acceptable salt thereof to said patient at a dailydosage of 2 mg, thereby limiting the risk of infection caused byvaricella zoster virus, wherein the relapsing remitting multiplesclerosis is treated by the administration of Siponimod.
 2. The methodaccording to claim 1, wherein treating comprises reducing the frequencyof clinical exacerbations.
 3. The method according to claim 1, whereinSiponimod is administered as a hydrochloride salt.
 4. The methodaccording to claim 1, wherein the infection is chickenpox.
 5. A methodfor treating multiple sclerosis in a patient in need thereof, the methodcomprising: (a) identifying a patient suffering from multiple sclerosisat risk of contracting infection caused by varicella zoster virus bytesting said patient for a history of infection caused by varicellazoster virus, (b) vaccinating the patient at risk of contractinginfection caused by varicella zoster virus, and (c) administering orallya therapeutically effective amount of Siponimod or a pharmaceuticallyacceptable salt thereof to said patient, thereby limiting the risk ofinfection caused by varicella zoster virus, wherein the multiplesclerosis is treated by the administration of Siponimod.
 6. The methodof claim 5, wherein the multiple sclerosis is primary progressivemultiple sclerosis.
 7. The method of claim 5, wherein the Siponimod isadministered in a dosage of 0.25 mg twice per day.
 8. The method ofclaim 5, wherein the Siponimod is administered in a dosage of 2 mg perday.